Intimal or Neointima formation underlies a number of common vascular diseases, including vascular graft stenosis and restenosis after an angioplasty or stent. Despite decades of investigations, the origin of neointima still remains controversial with studies variously pointing to the role of medial smooth muscle cell (SMC) proliferation (Costa M A and Simon D L Circulation, 111(17):2257 (2005)), vessel wall inflammation (Ohtani K, et al. Circulation. 110(16):2444 (2004)) and adventitial angiogenesis (Khurana R, et al. Circulation, 110(16):2436 (2004)).
Neointimal stenosis followed by thrombosis is the major cause of synthetic vascular graft failure. Tissue engineered vascular grafts (TEVGs) offer many advantages to these synthetic grafts, but also have limitations of their own. TEVGs are typically prepared by seeding autologous cells onto a biodegradable polymeric tubular scaffold. The scaffold degrades by hydrolysis, ultimately leaving only the living vessel in the patient.
The methodology of seeding synthetic vascular grafts with autologous cells, however, is still problematic for many reasons. First, it requires an invasive procedure (biopsy) in addition to the need for a substantial period of time in order to expand the cells in culture that limited its clinical utility. This approach also faces the inherent difficulty in obtaining healthy autologous cells from diseased donors (Poh, et al., Lancet, 365:2122-24 (2005); Solan, et al., Cell Transplant., 14(7):481-8 (2005)). The use of cell culture also results in an increased risk of contamination and even the potential for dedifferentiation of the cultured cells. The use of autologous cells to seed the polymeric grafts also limits the off-the-shelf availability of tissue engineered vascular grafts, thereby limiting their overall clinical utility. TEVGs that do not require cell seeding would offer many therapeutic, economic, and safety advantages.
It is an object of the invention to provide compositions and methods for treating and preventing neointimal stenosis.
It is a further object of the invention to provide methods for increasing the patency of biodegradable, synthetic vascular grafts with or without using cell seeding.
It is a further object of the invention to provide a cell-free TEVG with improved patency and reduced graft stenosis.